RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells

Angelamaria Rizzo, Martina Di Giovangiulio, Carmine Stolfi, Eleonora Franzè, Hans-Joerg Fehling, Rita Carsetti, Ezio Giorda, Alfredo Colantoni, Angela Ortenzi, Massimo Rugge, Claudia Mescoli, Giovanni Monteleone, Massimo C Fantini

Research output: Contribution to journalArticle

Abstract

Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor RORγt accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. RORγt+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific RORγt conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. RORγt expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional RORγt knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. RORγt-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of RORγt-deficient mice restored IL6 expression and tumor growth. These data demonstrate that RORγt expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. Cancer Immunol Res; 6(9); 1082-92. ©2018 AACR.

Original languageEnglish
Pages (from-to)1082-1092
Number of pages11
JournalCancer immunology research
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 2018

Fingerprint

Colitis
Dendritic Cells
Colorectal Neoplasms
Interleukin-6
Growth
Neoplasms
Inflammatory Bowel Diseases
Knockout Mice
Small Interfering RNA
Transcription Factors
Azoxymethane
Dextran Sulfate
Population Dynamics
Microinjections
Regulatory T-Lymphocytes
Mucous Membrane
Cytokines
Inflammation
Phenotype
Incidence

Cite this

RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells. / Rizzo, Angelamaria; Di Giovangiulio, Martina; Stolfi, Carmine; Franzè, Eleonora; Fehling, Hans-Joerg; Carsetti, Rita; Giorda, Ezio; Colantoni, Alfredo; Ortenzi, Angela; Rugge, Massimo; Mescoli, Claudia; Monteleone, Giovanni; Fantini, Massimo C.

In: Cancer immunology research, Vol. 6, No. 9, 09.2018, p. 1082-1092.

Research output: Contribution to journalArticle

Rizzo, A, Di Giovangiulio, M, Stolfi, C, Franzè, E, Fehling, H-J, Carsetti, R, Giorda, E, Colantoni, A, Ortenzi, A, Rugge, M, Mescoli, C, Monteleone, G & Fantini, MC 2018, 'RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells', Cancer immunology research, vol. 6, no. 9, pp. 1082-1092. https://doi.org/10.1158/2326-6066.CIR-17-0698
Rizzo, Angelamaria ; Di Giovangiulio, Martina ; Stolfi, Carmine ; Franzè, Eleonora ; Fehling, Hans-Joerg ; Carsetti, Rita ; Giorda, Ezio ; Colantoni, Alfredo ; Ortenzi, Angela ; Rugge, Massimo ; Mescoli, Claudia ; Monteleone, Giovanni ; Fantini, Massimo C. / RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells. In: Cancer immunology research. 2018 ; Vol. 6, No. 9. pp. 1082-1092.
@article{6215923c4e38451cb9b2153674384cbc,
title = "RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells",
abstract = "Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor RORγt accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. RORγt+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific RORγt conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. RORγt expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional RORγt knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. RORγt-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of RORγt-deficient mice restored IL6 expression and tumor growth. These data demonstrate that RORγt expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. Cancer Immunol Res; 6(9); 1082-92. {\circledC}2018 AACR.",
author = "Angelamaria Rizzo and {Di Giovangiulio}, Martina and Carmine Stolfi and Eleonora Franz{\`e} and Hans-Joerg Fehling and Rita Carsetti and Ezio Giorda and Alfredo Colantoni and Angela Ortenzi and Massimo Rugge and Claudia Mescoli and Giovanni Monteleone and Fantini, {Massimo C}",
note = "{\circledC}2018 American Association for Cancer Research.",
year = "2018",
month = "9",
doi = "10.1158/2326-6066.CIR-17-0698",
language = "English",
volume = "6",
pages = "1082--1092",
journal = "Cancer immunology research",
issn = "2326-6066",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - RORγt-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells

AU - Rizzo, Angelamaria

AU - Di Giovangiulio, Martina

AU - Stolfi, Carmine

AU - Franzè, Eleonora

AU - Fehling, Hans-Joerg

AU - Carsetti, Rita

AU - Giorda, Ezio

AU - Colantoni, Alfredo

AU - Ortenzi, Angela

AU - Rugge, Massimo

AU - Mescoli, Claudia

AU - Monteleone, Giovanni

AU - Fantini, Massimo C

N1 - ©2018 American Association for Cancer Research.

PY - 2018/9

Y1 - 2018/9

N2 - Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor RORγt accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. RORγt+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific RORγt conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. RORγt expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional RORγt knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. RORγt-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of RORγt-deficient mice restored IL6 expression and tumor growth. These data demonstrate that RORγt expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. Cancer Immunol Res; 6(9); 1082-92. ©2018 AACR.

AB - Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor RORγt accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. RORγt+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific RORγt conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. RORγt expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional RORγt knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. RORγt-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of RORγt-deficient mice restored IL6 expression and tumor growth. These data demonstrate that RORγt expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. Cancer Immunol Res; 6(9); 1082-92. ©2018 AACR.

U2 - 10.1158/2326-6066.CIR-17-0698

DO - 10.1158/2326-6066.CIR-17-0698

M3 - Article

C2 - 29991500

VL - 6

SP - 1082

EP - 1092

JO - Cancer immunology research

JF - Cancer immunology research

SN - 2326-6066

IS - 9

ER -